Preserved cyclodextrin-containing compositions

ABSTRACT

Compositions including a liquid medium, a cyclodextrin component and a preservative component which has a reduced tendency to being complexed with the cyclodextrin component. In one embodiment, the preservative component is a chlorite component. Active components, such as pharmaceutically active components or drugs, preferably are included in the compositions.

RELATED APPLICATION

[0001] This application claims benefit of Provisional Application Ser.No. 60/098,854 filed Sep. 2, 1998.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to preservedcyclodextrin-containing compositions. More particularly, the inventionrelates to cyclodextrin-containing compositions, for example, suchcompositions containing one or more pharmaceutically active components,including preservatives which have substantial preserving efficacy inthe presence of cyclodextrin components.

[0003] Cyclodextrins are widely known in the literature to increase thesolubility of poorly water soluble pharmaceuticals or drugs and/orenhance pharmaceutical/drug stability and/or reduce unwanted sideeffects of pharmaceuticals/drugs. For example, steroids, which arehydrophobic, often exhibit an increase in water solubility of one orderof magnitude or more in the presence of cyclodextrins. However, onesubstantial problem with pharmaceutical compositions includingcyclodextrins, particularly such compositions in multi-dose formats, hasto do with preserving such compositions. Typical preservatives arerelatively ineffective at normal concentrations in such compositions,that is the compositions including such preservatives are unable to meetor pass standard preservative efficacy tests. It is believed that thepreservative becomes complexed with the cyclodextrin and is renderedineffective or has reduced effectiveness as a preservative.

[0004] It would be advantageous to provide cyclodextrin-containingcompositions which are effectively preserved.

SUMMARY OF THE INVENTION

[0005] New cyclodextrin-containing compositions have been discovered.Such compositions include preservatives which are effective andefficacious in the presence of cyclodextrins. Preferably, thepreservatives are present in the compositions in amounts to provideacceptable preservative efficacy and, in addition, are sufficientlyinnocuous or non-toxic so that the compositions can be administered tohumans or animals to obtain desired therapeutic effects withoutsignificant detriment resulting from the presence of the preservatives.For example, the present compositions may include a pharmaceuticaleffective in providing a therapeutic effect when administered to theeyes of a human or animal. The preservative employed is preferablyophthalmically acceptable at the concentration employed so that thehuman or animal is effectively treated without significant harm causedby the presence of the preservative.

[0006] In short, the present compositions effectively take advantage ofcyclodextrin components, e.g., in increasing the apparent watersolubility of pharmaceuticals, and are effectively preserved andpreferably substantially non-toxic in use.

[0007] In one broad aspect of the present invention, compositions areprovided which comprise a liquid medium, a cyclodextrin component, forexample, in an amount in the range of about 0.1% to about 30% (w/v), anda preservative component in an effective preserving amount, preferablyof less than about 1% (w/v) or about 0.8% (w/v) and may be in the rangeof about 10 ppm(w/v) or less to about 200 ppm(w/v). In one embodiment,the preservative component has sufficient preservative efficacy so thatthe composition including such preservative component passes one or morestandard preservative efficacy tests, such as in the United StatesPreservative Efficacy Test (USPET), the European Preservative EfficacyTest-A (EP-A), the European Preservative Efficacy Test-B (EP-B), and thelike standard tests.

[0008] Preferably, the preservative component has an increased orgreater preservative efficacy in the present composition relative to anidentical amount (w/v) of benzalkonium chloride. Benzalkonium chloride,which is a preservative that is often used in pharmaceuticalcompositions, is relatively ineffective at typical concentrations incompositions including cyclodextrin component. It is believed that thebenzalkonium chloride complexes with the cyclodextrin component. Thiscomplex renders the benzalkonium chloride antimicrobially ineffective.Thus, benzalkonium chloride has a reduced preservative efficacy in thepresence of cyclodextrin component. More preferably, the presentpreservative component forms a complex with the cyclodextrin component,if at all, to a lesser extent than does benzalkonium chloride.

[0009] The present compositions preferably are substantially free ofinclusion complexes of the cyclodextrin component and the preservativecomponent.

[0010] Using a preservative component in accordance with the presentinvention which is substantially not affected by the cyclodextrincomponent allows the preservative component to be more efficacious as apreservative. Alternately, reduced amounts of the preservative componentcan be used to achieve acceptable preservative results. Such reducedamounts of preservative components reduce the toxicity or sensitivityfor the composition as it is being administered to a human or animal.

[0011] Any suitable preservative component which functions as describedherein is included within the scope of the present invention. Thepreservative efficacy tests identified herein are standard tests whichcan be easily and routinely conducted on any prospective preservativecomponent to determine if such preservative component meets thecriteria. Of course, the present preservative components should have nosubstantial detrimental effect on the composition or the activecomponent or components of the composition or the use of the compositionor the human or animal to whom the composition is administered. Tests todetermine whether a prospective preservative component meets thesecriteria are well known and can be routinely conducted. In other words,one of ordinary skill in the art can determine, without undueexperimentation, whether or not any prospective preservative componentis within the scope of the preservative components of the presentinvention.

[0012] In one particularly useful embodiment, the present preservativecomponent is selected from chlorite components, sorbic acid componentsand mixtures thereof present in an effective preserving amount. Morepreferably, the preservative component is selected from stabilizedchlorine dioxide, alkali metal chlorites, sorbic acid, alkali metalsorbates and mixtures thereof. Chlorite components are very effective inthe present compositions since they achieve preservative effectivenessat a relatively reduced concentration. Both the chlorite components andsorbic acid components are effective preservatives in the presence ofcyclodextrin. Without wishing to limit the invention to any particulartheory of operation, it is believed that the chlorite components and thesorbic acid components are substantially free in the presence of thecyclodextrin component or are substantially not complexed with thechlorodextrin component.

[0013] In another broad aspect of the present invention, compositionsare provided which comprise a liquid medium, an active component, acyclodextrin component and a preservative component. The activecomponent is present in an amount effective in providing a desiredeffect to a human or an animal after the composition is administered tothe human or animal. The cyclodextrin component preferably is present inan amount effective to increase the apparent solubility of the activecomponent in the liquid medium and/or enhance the stability of theactive component in the composition and/or reduce unwanted side effectsof the acting component in the composition. The preservative componentis present in an effective preserving amount, preferably less than about1% (w/v) or about 0.8% (w/v) and may be in the range of about 10ppm(w/v) or less to about 200 ppm(w/v). The preservative component is asidentified elsewhere herein.

[0014] The present compositions which include active components,preferably pharmaceutically active components, as described herein, areparticularly useful in multi-dose formats in which preservative efficacyis particularly important. Thus, such compositions obtain the advantagesof cyclodextrin components, for example, in enhancing the solubility ofthe active components and, in addition, include effective preservativecomponents, preferably at concentrations which reduce the risk ofcausing any substantial or significant harm or detriment to the humansor animals to whom the compositions are administered as a result of thepresence of the preservative components.

[0015] Any feature or combination of features described herein areincluded within the scope of the present invention provided that thefeatures included in any such combination are not mutually inconsistent.

[0016] Additional advantages and aspects of the present invention areapparent in the following detailed description and claims.

DETAILED DESCRIPTION

[0017] The present compositions include liquid media, cyclodextrincomponents, and preservative components. Preferably, the presentcompositions further include active components, more preferablypharmaceutically active components. The present compositions can havethe characteristics of simple liquid, for example, aqueous liquid,solutions.

[0018] Any suitable cyclodextrin component may be employed in accordancewith the present invention. The useful cyclodextrin components include,but are not limited to, those materials which are effective inincreasing the apparent solubility, preferably water solubility, ofpoorly soluble active components and/or enhance the stability of theactive components and/or reduce unwanted side effects of the activecomponents. Examples of useful cyclodextrin components include, but arenot limited to: α-cyclodextrin, derivatives of α-cyclodextrin,β-cyclodextrin, derivatives of β-cyclodextrin, γ-cyclodextrin,derivatives of γ-cyclodextrin, carboxymethyl-β-cyclodextrin,carboxymethyl-ethyl-β-cyclodextrin, diethyl-β-cyclodextrin,dimethyl-β-cyclodextrin, methyl-β-cyclodextrin, randommethyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin,hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin,sulfobutylether-β-cyclodextrin, and the like and mixtures thereof. Asused herein, the term “derivatives” as it relates to a cyclodextrinmeans any substituted or otherwise modified compound which has thecharacteristic chemical structure of a cyclodextrin sufficiently tofunction as a cyclodextrin component, for example, to enhance thesolubility and/or stability of active components and/or reduce unwantedside effects of the active components and/or to form inclusive complexeswith active components, as described herein.

[0019] The specific cyclodextrin component selected should haveproperties acceptable for the desired application. The presentcompositions, and therefore the cyclodextrin component, may be appliedtopically and/or systemically. Topical application is preferred. Incertain situations, the cyclodextrin component should have or exhibitreduced toxicity, particularly if the composition is to be exposed tosensitive body tissue, for example, eye tissue, etc. Very usefulcyclodextrin components include β-cyclodextrin, derivatives ofβ-cyclodextrin and mixtures thereof. Particularly useful cyclodextrincomponents include sulfobutylether β-cyclodextrin, hydroxypropylβ-cyclodextrin and mixtures thereof. Sulfobutylether β-cyclodextrin isespecially useful, for example, because of its substantially reducedtoxicity.

[0020] The amount of cyclodextrin component in the present compositionsis not of critical importance. Such amount should be effective toperform the desired function or functions in the present compositionand/or after administration to the human or animal. The amount ofcyclodextrin component preferably is sufficient to complex at least inmajor amount, and more preferably substantially all, of the activecomponent in the present composition. In one useful embodiment, theamount of cyclodextrin component in the present composition is in therange of about 0.1% to about 30% (w/v) or more of the composition.

[0021] The present preservative components are selected so as to beeffective and efficacious as preservatives in the present compositions,that is in the presence of cyclodextrin components, and preferably havereduced toxicity and more preferably substantially no toxicity when thecompositions are administered to a human or animal.

[0022] As stated above, preservatives which are commonly used inpharmaceutical compositions are often less effective when used in thepresence of cyclodextrins. In certain instances, this reducedpreservative efficacy can be compensated for by using increased amountsof the preservative. However, where sensitive or delicate body tissue isinvolved, this approach may not be available since the preservativeitself may cause some adverse reaction or sensitivity in the human oranimal, to whom the composition is administered.

[0023] Preferably, the present preservative components are effective inconcentrations of less than about 1% (w/v) or about 0.8% (w/v) and maybe 500 ppm (w/v) or less, for example, in the range of about 10 ppm(w/v)or less to about 200 ppm(w/v). In one embodiment, the presentpreservative components have greater preservative efficacy in thecomposition relative to an identical amount (w/v) of benzalkoniumchloride in the presence of the cyclodextrin component. Testing todetermine comparative preservative efficacy is well known and can beroutinely conducted. Preservative components in accordance with thepresent invention preferably include, but are not limited to, thosewhich form complexes with the cyclodextrin component to a lesser extentthan does benzalkonium chloride.

[0024] Very useful examples of the present preservative componentsinclude, but are not limited to, chlorite components, sorbic acidcomponents and mixtures thereof.

[0025] Specific examples of chlorite components useful as preservativesin accordance with the present invention include stabilized chlorinedioxide (SCD), metal chlorites, such as alkali metal and alkaline earthmetal chlorites, and the like and mixtures therefor. Technical grade (orUSP grade) sodium chlorite is a very useful preservative component. Theexact chemical composition of many chlorite components, for example,SCD, is not completely understood. The manufacture or production ofcertain chlorite components is described in McNicholas U.S. Pat. No.3,278,447, which is incorporated in its entirety herein by reference.Specific examples of useful SCD products include that sold under thetrademark Dura Klor by Rio Linda Chemical Company, Inc., and that soldunder the trademark Anthium Dioxide by International Dioxide, Inc. Anespecially useful SCD is a product sold under the trademark Purogene® byBio-Cide International, Inc.

[0026] Specific examples of sorbic acid components useful aspreservatives in accordance with the present invention include sorbicacid itself, as well as pharmaceutically and/or ophthalmicallyacceptable sorbic acid derivatives and mixture thereof. Useful sorbicacid components include, but are not limited to, metal sorbates, such asalkali metal and alkaline earth metal sorbates, and the like andmixtures thereof. If a sorbic acid component is employed as apreservative in accordance with the present invention, the compositionadvantageously has a pH of less than about 7, for example in the rangeof about 3 or about 4 to less than 7. Such pH conditions increase theantimicrobial effectiveness of the sorbic acid component so thatsomewhat reduced concentrations of the sorbic acid component may beeffectively employed. Of course, it is not essential that thecomposition have a pH of less than 7.

[0027] The preservative component may be included in the composition ata predetermined concentration, e.g., to provide an effective preservingamount of preservative component in the composition. For example, if achlorite component is employed as a preservative in accordance with thepresent invention, the concentration of the chlorite componentpreferably is less than about 500 ppm (w/v), and more preferably is inthe range of about 10 ppm (w/v) or less to about 200 ppm (w/v). If asorbic acid component is employed as a preservative, the concentrationof the sorbic acid component preferably is in the range of less thanabout 1% (w/v) or about 0.8% (w/v), and more preferably is in a range ofabout 0.05% (w/v) or less to about 0.8% (w/v).

[0028] The presently useful active components preferably are chosen tobenefit from the presence of the cyclodextrin components. In general,the active components are provided with increased apparent solubility,preferably increased apparent water solubility, by the presence of thecyclodextrin components. Without wishing to limit the invention to anyparticular theory of operation, it is believed that the activecomponents form inclusion or clathrate complexes with the cyclodextrincomponents.

[0029] Examples of the pharmaceutically active component which may bebenefitted by the presence of cyclodextrin components in the presentinvention include, but are not limited to, diphenyl hydantoin,adiphenine, allobarbital, aminobenzoic acid, amobarbital, ampicillin,anethole, aspirin, azopropazone, azulene barbituric acid,beclomethasone, beciomethasone dipropronate, bencyclane, benzaldehyde,benzocaine, benzodiazepines, benzodiazepines, benzothiazide,betamethasone, betamethasone 17-valerate, bromobenzoic acidbromoisovalerylurea, butyl-p-aminobenzoate, chloralhydrate,chlorambucil, chloramphenicol, chlorobenzoic acid, chlorpromazine,cinnamic acid, clofibrate, coenzyme A, cortisone, cortisone acetate,cyclobarbital, cyclohexyl anthranilate, deoxycholic acid, dexamethasone,dexamethasone acetate, diazepam, digitoxin, digoxin, estradiol,flufenamic acid, fluocinolone acetonide, 5-fluorouracil, flurbiprogen,griseofulvin, guaiazulene, hydrocortisone, hydrocortisone acetate,ibuprofen, indican, indomethacin, iodine, ketoprofen, lankacidin-groupantibiotics, mefenamic acid, menadione, mephobarbital, methbarbital,methicillin, metronidazole, mitomycin, nitrazepam, nitroglycerin,nitrosureas, paramethasone, penicillin, pentobarbital, phenobarbital,phenobarbitone, phenyl-butyric acid, phenyl-valeric acid, phenytoin,prednisolone, prednisolone acetate, prednisone, progesterone,propylparaben, proscillaridin, prostaglandin A series, prostaglandin Bseries, prostaglandin E series, prostaglandin F series, quinolineanti-microbials reserpine, spironolactone, sulfacetamide sodium,sulfonamide, androgens, including but not limited to testosterone,thalidomide, thiamine dilaurylsulphate, thiamphenicolpalmitate,thiopental, triamcinolone, vitamin A, vitamin D3, vitamin E, vitamin K3,and warfarin.

[0030] The complexes may be prepared by any method known in the art forthe preparation of complexes of cyclodextrin components. For example,the active component and cyclodextrin component may be dissolved inwater or an organic solvent (either miscible or immiscible with water).Convenient solvents include for example diethylether, tetrahydrofuran,dioxane, acetone, dimethylsulfoxide, dimethylformamide and loweraliphatic alcohols. Preferably the active component is dissolved ineither water or a mixture of water and a water-miscible solvent such asmethanol or ethanol. The active component may also be suspended inwater.

[0031] After equilibrium is reached, the complex may be isolated by anysuitable technique for example, lyophilization, evaporation of thesolvent, precipitation, low temperature crystallization, orspraγ-drying. Cyclodextrin inclusion complexes may also be produced byphysically grinding or kneading the cyclodextrin component and theactive component with or without a small amount of solvent. The ratio ofcyclodextrin component to active component used to prepare the complexesmay be any convenient ratio but the cyclodextrin component preferably isused in a molar excess.

[0032] Benefits may be obtained by having the molar ratio ofcyclodextrin component to active component in the range of about 10:1 toabout 1:1 or less, preferably about 5:1 or about 3:1 or about 2:1 toabout 1:1 or less and by using the methods and ratios described above.Complexes are conveniently obtained containing up to 20% w/w of theactive component. However, in view of the low doses of the drug normallyadministered and the difficulty of preparing homogenous mixtures ofactive ingredient and excipients it may be desirable to prepare thecomplex with an excess of the cyclodextrin component present, forexample, complexes containing in the order of about 0.001% to about 10%by weight of the active component.

[0033] The liquid media useful in the present invention are selected tohave no substantial detrimental effect on the present compositions, onthe use of the compositions or on the human or animal to whom thecompositions are administered. The liquid media are preferablyaqueous-based. One useful aqueous liquid medium is that derived fromsaline, for example, a conventional saline solution or a conventionalbuffered saline solution. The aqueous liquid medium preferably has a pHin the range of about 4 or about 6 to about 9 or about 10, morepreferably about 6 to about 8. In one embodiment, liquid mediumpreferably has a ophthalmically acceptable tonicity level, for example,of at least about 200 m0smol/kg, more preferably in the range of about200 to about 600 mosmol/kg.

[0034] In order to insure that the pH of the aqueous liquid medium ismaintained within the desired range, the aqueous liquid medium mayinclude at least one buffer component. It is preferred that the buffercomponent be inorganic. Alkali metal and alkaline earth metal buffercomponents are advantageously used in the present invention.

[0035] Any suitable ophthalmically acceptable tonicity component orcomponents may be employed, provided that such component or componentsare compatible with the other ingredients of the liquid medium and donot have deleterious or toxic properties which could harm the human oranimal to whom the present compositions are administered. Example ofuseful tonicity components include sodium chloride, potassium chloride,mannitol, dextrose, glycerin, propylene glycol and mixtures thereof. Inone embodiment, the tonicity component is selected from inorganic saltsand mixtures thereof.

[0036] The present compositions may conveniently be presented assolutions or suspensions in aqueous liquids or non-aqueous liquids, oras oil-in-water or water-in-oil liquid emulsions. The presentcompositions may include one or more additional ingredients such asdiluents, flavoring agents, surface active agents, thickeners,lubricants, and the like, for example, such additional ingredients whichare conventionally employed in compositions of the same general type.

[0037] The present compositions in the form of aqueous suspensions mayinclude excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gun tragacanth and gun acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example, lecithin, or condensation products of ethylene oxide withlong chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol,or condensation products of ethylene oxide with partial esters derivedfrom fatty acids and a hexitol such as polyoxyethylene sorbitolmono-oleate, or condensation products of ethylene oxide with partialesters derived from fatty acids and hexitol anhydrides, for example,polyoxyethylene sorbitan mono-oleate, and the like and mixtures thereof.Such aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents and one or more sweetening agents, such assucrose, saccharin, and the like and mixtures thereof.

[0038] The present compositions in the form of oily suspensions may beformulated in a vegetable oil, for example, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. Suchsuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation.

[0039] The present compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, for example, olive oilor arachis oil, or a mineral oil, for example, liquid paraffin, and thelike and mixtures thereof. Suitable emulsifying agents may benaturallγ-occurring gums, for example, gum acacia or gun tragacanth,naturallγ-occurring phosphatides, for example, soya bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan mono-oleate, and condensation productsof the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan mono-oleate. The emulsions may also containsweetening and flavoring agents.

[0040] The present compositions in the form of syrups and elixirs may beformulated with sweetening agents, for example, as described elsewhereherein. Such formulations may also contain a demulcent, and flavoringand coloring agents.

[0041] The specific dose level for any particular human or animaldepends upon a variety of factors including the activity of the activecomponent employed, the age, body weight, general health, sex, diet,time of administration, route of administration, rate of excretion, drugcombination and the severity of the particular condition undergoingtherapy.

[0042] The active component in the present compositions may beadministered at dosage levels and dosage intervals required to achievethe desired therapeutic effect normally associated with the activecomponent and the disease or condition state in absence of thecyclodextrin component.

[0043] The following non-limiting examples illustrate certain aspects ofthe present invention. EXAMPLES 1 AND 2 Two (2) aqueous compositionswere prepared by blending together the following components: ComponentsComposition 1 Composition 2 Sodium chloride 0.62% (w/v) 0.62% (w/v)Potassium chloride 0.14% (w/v) 0.14% (w/v) Calcium chloride (dihydrate)0.02% (w/v) 0.02% (w/v) Magnesium chloride 0.006% (w/v) 0.006% (w/v)(hexahydrate) Sodium carboxy- 0.5% (w/v) 0.5% (w/v) methylcelluloseBoric acid 0.2% (w/v) 0.2% (w/v) Sodium borate (decahydrate) 0.14% (w/v)0.14% (w/v) Brimodine tartarate⁽¹⁾ 0.2% (w/v) 0.2% (w/v) Stabilizedchlorine dioxide⁽²⁾ 50 ppm (w/v) 50 ppm (w/v) Sulfobutylether βcyclodextrin — 1% (w/v) Water, USP Q.S. to volume Q.S. to volume pH 7.47.4

[0044] Each of these compositions was tested for preservative efficacyin accordance with (1) United States Preservative Efficacy Test (USPET)test criteria; (2) European Preservative Efficacy-A (EP-A) testcriteria; and (3) European Preservative-B (EP-B) test criteria. Thesetest criteria are well known and conventionally utilized to determinethe preservative efficacy of any given preservative or preservedcomposition.

[0045] The test results for each of these compositions is set forth inthe following table. Composition USPET EP-A EP-B 1 Pass Fail Fail 2 PassFail Pass

[0046] These test results show that Composition 1 passes the USPET testcriteria, and fails the EP-A and EP-B test criteria. The EP-B criteriawere failed marginally by Composition 1 against C. Albicans. It isbelieved that composition 1 may pass the EP-B test criteria upon retest.

[0047] Composition 2 passes both the USPET and the EP-B test criteriaand fails only the more strict EP-A test criteria.

[0048] These results demonstrate that the presence of a cyclodextrincomponent (Composition 2) does not have any detrimental effect on thepreservative efficacy of stabilized chlorine dioxide, a chloritecomponent. These results indicate that the stabilized chlorine dioxideremains free and effective as a preservative in Composition 2, ratherthan being complexed by the cyclodextrin component and thus inhibited inproviding preservative efficacy.

[0049] Composition 2, in accordance with the present invention, isophthalmically acceptable and effective in providing therapeutic effectsresulting from the presence of the brimonidine tartarate. The presenceof the cyclodextrin component in Composition 2 enhances the effective orapparent water solubility of the brimonidine tartarate, substantiallywithout detrimentally causing increased toxicity, for example, whenadministered to a patient in need of the therapeutic effects provided bybrimonidine tartarate.

EXAMPLES 3 TO 9 Comparative

[0050] A series of seven (7) aqueous compositions were prepared byblending together the following components: Benzalkonium HydroxybutylComposition Chloride β cyclodextrin Water pH 3  50 ppm (w/v) 20% (w/v)Q.S. to vol. 8.0 4 100 ppm (w/v) 20% (w/v) Q.S. to vol. 8.0 5  50 ppm(w/v) 10% (w/v) Q.S to vol. 7.2 6  50 ppm (w/v) 10% (w/v) Q.S. to vol.8.0 7  50 ppm (w/v) 10% (w/v) Q.S. to vol. 8.0 8  50 ppm (w/v) — Q.S. tovol. 7.2 9  50 ppm (w/v) — Q.S. to vol. 8.0

[0051] Each of these aqueous compositions was tested for preservativeefficacy in accordance with the USPET test criteria. Results of thesetests are summarized in the following table. Composition USPET Results 3Fail 4 Fail 5 Fail 6 Fail 7 Fail 8 Pass 9 Pass

[0052] These test results indicate that benzalkonium chloride isineffective as a preservative when used in compositions includingcyclodextrin components. Without wishing to limit the invention to anyparticular theory of operation, it is believed that the cyclodextrincomponent complexes the benzalkonium chloride sufficiently to inhibit oreven prevent the benzalkonium chloride from being an effectivepreservative.

[0053] These results are in substantial contrast to the results setforth in Examples 1 and 2 in which stabilized chlorine dioxide is shownto be an effective preservative with or without a cyclodextrincomponent.

EXAMPLES 10 TO 21

[0054] A series of twelve (12) aqueous compositions were prepared byblending together the following components: Composition ⁽¹⁾ 10 11 12 1314 15 Prednisolone — — — — 0.1 0.1 Acetate, w/v % Sulfobutyletherβ-cyc1odextrin, w/v % — — 8.0 8.0 8.0 8.0 Benzalkonium 0.15 .0075 0.15.0075 0.15 .0075 chloride, w/v % Stabilized chlorine — — — — — — dioxide⁽²⁾, w/v % Composition ⁽¹⁾ 16 17 18 19 20 21 Prednisolone — — — — 0.10.1 Acetate, w/v % Sulfobutylether — — 8.0 8.0 8.0 8.0 β-cyclodextrin,w/v % Benzalkonium — — — — — — chloride, w/v % Stabilized chlorine 0.15.0075 0.15 .0075 0.15 .0075 dioxide ⁽²⁾, w/v %

[0055] Each of these compositions was tested for preservative efficacyin accordance with (1) United States Preservative Efficacy Test (USPET)test criteria; (2) European Preservative Efficacy-A (EP-A) testcriteria; and (3) European Preservative-B (EP-B) test criteria.

[0056] The test results for each of these compositions is set forth inthe following table. Composition USPET EP-A EP-B 10 Pass Pass Pass 11Pass Pass Pass 12 Fail Fail Fail 13 Fail Fail Fail 14 Fail Fail Fail 15Fail Fail Fail 16 Pass Fail Fail 17 Pass Fail Fail 18 Pass Fail Fail 19Pass Fail Fail 20 Pass Fail Fail 21 Pass Fail Fail

[0057] Compositions 10 and 11, which include only benzalkonium chloride,pass all of the preservative efficacy criteria. On the other hand,compositions 12 to 15, which include benzalkonium chloride and thecyclodextrin fail all preservative efficacy criteria. The addition ofprednisolone acetate does not help to increase the antimicrobialactivity, except for the activity against S. Aureus. All of thesolutions, that is Compositions 16 to 21, containing stabilized chlorinedioxide pass the USPET. Compositions containing only stabilized chlorinedioxide, that is Compositions 16 and 17, fail the EP-A and EP-B tests onfungi only. When the cyclodextrin is added to the compositions includingstabilized chlorine dioxide, Compositions 18 to 21, the antimicrobialactivity is decreased. Compositions containing stabilized chlorinedioxide, the cyclodextrin, and prednisolone acetate, Compositions 20 and21, fail the EP-A and EP-B criteria for the fungi only. The compositionsincluding stabilized chlorine dioxide only fail the EP-B test only forA. Niger.

[0058] Although the presence of the cyclodextrin component does resultin a decrease in the antimicrobial activity of the compositions, thecombination of the cyclodextrin component and stabilized chlorinedioxide, a chlorite component, passes the preservative efficacy testspassed by compositions including only stabilized chlorine dioxide. Theseresults indicate that a substantial portion of the stabilized chlorinedioxide remains free or not complexed by the cyclodextrin and effectiveas a preservative rather than being complexed by the cyclodextrincomponent and thus inhibited in providing preservative efficacy.

EXAMPLES 22 TO 29

[0059] A series of eight (8) aqueous compositions were prepared byblending together the following components: Composition⁽¹⁾ 22 23 24 25Prednisolone 0.1 0.1 0.1 0.1 Acetate, w/v % Sulfobutylether 8.0 8.0 8.08.0 β-cyclodextrin, w/v % Benzalkonium 0.15 0.15 0.15 0.15 chloride, w/v% Stabilized chlorine — — — — dioxide⁽²⁾, w/v % Potassium .05 .5 — —sorbate, w/v % Glycerin, w/v % — — 2.0 — Propyl glycol, w/v % — — — 2.0Composition⁽¹⁾ 26 27 28 29 Prednisolone 0.1 0.1 0.1 0.1 Acetate, w/v %Sulfobutylether 8.0 8.0 8.0 8.0 β-cyclodextrin, w/v % Benzalkonium — — —— chloride, w/v % Stabilized chlorine .0075 .0075 .0075 .0075dioxide⁽²⁾, w/v % Potassium .05 .5 — — sorbate, w/v % Glycerin, w/v% — —2.0 — Propyl glycol, w/v % — — — 2.0

[0060] Each of these compositions was tested for preservative efficacyin accordance with (1) United States Preservative Efficacy Test (USPET)test criteria; (2) European Preservative Efficacy-A (EP-A) testcriteria; and (3) European Preservative-B (EP-B) test criteria.

[0061] The test results for each of these compositions is set forth inthe following table. Composition USPET EP-A EP-B 22 Fail Fail Fail 23Fail Fail Fail 24 Fail Fail Fail 25 Fail Fail Fail 26 Pass Fail Fail 27Pass Fail Pass 28 Pass Fail Fail 29 Pass Fail Fail

[0062] These results indicate that all benzylkonium chloride-containingcompositions fail all of the USPET, EP-A and EP-B criteria.

[0063] With regard to compositions including stabilized chlorinedioxide, Compositions 26, 28 and 29 fail the EP-A and EP-B criteriabecause of either or both C. albicans and A. niger or just a niger. Eachof these compositions pass the USPET criteria. Composition 27 showsinteresting results. This composition fails the EP-A criteria for C.albicans and A. niger, but passes both USPET and EP-B criteria. Uponrepeat of the test, the composition passes the EP-A criteria.

[0064] The potassium sorbate even has an effect on the benzalkoniumchloride-containing composition, that is Composition 23. Composition 23still fails the USPET criteria, but only because of E. coli and A.niger. Other samples fail because of P. aerogenosa. Thus, the potassiumsorbate is providing enhanced preservative efficacy in compositionsincluding benzalkonium chloride.

EXAMPLES 30 TO 33

[0065] A series of four (4) aqueous compositions were prepared byblending together the following components: Composition⁽¹⁾ 30 31 32 33Prednisolone — 0.1 0.1 0.1 Acetate, w/v % Sulfobutylether — 8.0 8.0 8.0β-cyclodextrin, w/v % Stabilized chlorine .0075 — — — dioxide⁽²⁾, w/v %Potassium — 0.5 0.5 0.5 sorbate, w/v % PH 7.4 6.5 5.5 4.5

[0066] Each of these compositions was tested for preservative efficacyin accordance with (1) United States Preservative Efficacy Test (USPET)test criteria; (2) European Preservative Efficacγ-A (EP-A) testcriteria; and (3) European Preservative-B (EP-B) test criteria.

[0067] The test results for each of these compositions is set forth inthe following table. Composition USPET EP-A EP-B 30 Pass Fail Fail 31Pass Fail Fail 32 Pass Fail Pass 33 Pass Pass Pass

[0068] These results indicate that cyclodextrin compositions includingeither stabilized chlorine dioxide or potassium sorbate pass the USPETcriteria. In particular, Compositions 31, 32 an 33 include bothpotassium sorbate and the cyclodextrin and pass the USPET criteria. Atsomewhat reduced pHs, as shown in Compositions 32 and 33, compositionsincluding potassium sorbate and cyclodextrin pass the EP-B criteria(Composition 32) and even the EP-B and EP-A criteria (Composition 33).

[0069] Without wishing to limit the invention to any particular theoryof operation, it is believed that the cyclodextrin component does notcomplex the sorbate component sufficiently to inhibit the sorbate fromacting as an effective preservative. Also, the sorbate at more acidicconditions is a more effective preservative component.

[0070] While this invention has been described with respect to variousspecific examples and embodiments, it is to be understood that theinvention is not limited thereto and that it can be variously practicedwith the scope of the following claims.

What is claimed is:
 1. A composition comprising: a liquid medium; acyclodextrin component in an amount in a range of about 0.1% to about30% (w/v); and a chlorite component in an effective preserving amount.2. The composition of claim 1 wherein the liquid medium is an aqueousliquid medium.
 3. The composition of claim 1 wherein the cyclodextrincomponent is selected from the group consisting of β-cyclodextrin,derivatives of β-cyclodextrin and mixtures thereof.
 4. The compositionof claim 1 wherein the chlorite component is present in an amount ofabout 500 ppm (w/v) or less.
 5. The composition of claim 1 wherein thechlorite component is present in an amount in a range of about 10 ppm(w/v) to about 200 ppm(w/v).
 6. The composition of claim 1 wherein thechlorite component is stabilized chlorine dioxide.
 7. The composition ofclaim 1 which further comprises an active component in an amounteffective in providing a desired effect to a human or an animal afterthe composition is administered to the human or animal.
 8. Thecomposition of claim 7 wherein the active component is apharmaceutically active component effective in providing a desiredtherapeutic effect to the human or animal after the composition isadministered to the human or animal.
 9. A composition comprising: aliquid medium; a cyclodextrin component in an amount in a range of about0.1% to about 30% (w/v); and a preservative component in an effectivepreserving amount, the preservative component having a greaterpreservative efficacy in the composition relative to an identical amountof benzalkonium chloride.
 10. The composition of claim 9 wherein thepreservative component forms a complex with the cyclodextrin componentto a lesser degree than benzalkonium chloride.
 11. The composition ofclaim 9 wherein the liquid medium is an aqueous liquid medium, and thepreservative component is present in an amount of less than about 0.8%(w/v).
 12. The composition of claim 9 wherein the preservative componentis present in an amount in a range of about 10 ppm(w/v) to about 200ppm(w/v).
 13. The composition of claim 10 wherein the cyclodextrincomponent is selected from the group consisting of β-cyclodextrin,derivatives of β-cyclodextrin and mixtures thereof.
 14. The compositionof claim 9 wherein the preservative component is selected from the groupconsisting of chlorite components, sorbic acid components and mixturesthereof.
 15. The composition of claim 9 wherein the preservativecomponent is stabilized chlorine dioxide.
 16. The composition of claim 9wherein the preservative component is selected from the group consistingof sorbic acid, sorbates and mixtures thereof.
 17. The composition ofclaim 9 which further comprises an active component in an amounteffective in providing a desired effect to a human or an animal afterthe composition is administered to the human or animal.
 18. Thecomposition of claim 17 wherein the active component is apharmaceutically active component effective in providing a desiredtherapeutic effect to the human or animal after the composition isadministered to the human or animal.
 19. The composition of claim 9which is substantially free of inclusion complexes of the cyclodextrincomponent and the preservative component.
 20. A composition comprising:a liquid medium; an active component in an amount effective in providinga desired effect to a human or an animal after the composition isadministered to the human or animal; a cyclodextrin component in anamount effective to increase the apparent solubility of the activecomponent in the liquid medium or to enhance the stability of the activecomponent in the composition or to reduce unwanted side effects of theactive component; and a preservative component in an effectivepreserving amount, the preservative component having greaterpreservative efficacy in the composition relative to an identical amountof benzalkonium chloride.
 21. The composition of claim 20 wherein theliquid medium is an aqueous liquid medium.
 22. The composition of claim20 wherein the active component is a pharmaceutically active componenteffective in providing a desired therapeutic effect to the human oranimal after the composition is administered to the human or animal. 23.The composition of claim 21 wherein the active component is apharmaceutically active component effective in providing a desiredtherapeutic effect to the human or animal after the composition isadministered to the human or animal.
 24. The composition of claim 20wherein the cyclodextrin component is selected from the group consistingof β-cyclodextrin, derivatives of β-cyclodextrin and mixtures thereof.25. The composition of claim 20 wherein the cyclodextrin component ispresent in an amount in a range of about 0.1% to about 30% (w/v). 26.The composition of claim 20 wherein the preservative component forms acomplex with the cyclodextrin component to a lesser degree than doesbenzalkonium chloride.
 27. The composition of claim 20 wherein thepreservative component is present in an amount of about 1% (w/v) orless.
 28. The composition of claim 20 wherein the preservative componentis present in an amount in a range of about 10 ppm(w/v) to about 200ppm(w/v).
 29. The composition of claim 20 wherein the preservativecomponent is selected from the group consisting of chlorite components,sorbic acid components and mixtures thereof.
 30. The composition ofclaim 29 wherein the preservative component is stabilized chlorinedioxide.